Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

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Woldegebriel , R , Kvist , J , Andersson , N , Ounap , K , Reinson , K , Wojcik , M H , Bijlsma , E K , Hoffer , M J , Ryan , M M , Stark , Z , Walsh , M , Cuppen , I , van den Boogaard , M-J H , Bharucha-Goebel , D , Donkervoort , S , Winchester , S , Zori , R , Bonnemann , C G , Maroofian , R , O'Connor , E , Houlden , H , Zhao , F , Carpen , O , White , M , Sreedharan , J , Stewart , M , Ylikallio , E & Tyynismaa , H 2020 , ' Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content ' , Human Molecular Genetics , vol. 29 , no. 9 , pp. 1426-1439 . https://doi.org/10.1093/hmg/ddaa051

Title: Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content
Author: Woldegebriel, Rosa; Kvist, Jouni; Andersson, Noora; Ounap, Katrin; Reinson, Karit; Wojcik, Monica H.; Bijlsma, Emilia K.; Hoffer, Mariette J.; Ryan, Monique M.; Stark, Zornitza; Walsh, Maie; Cuppen, Inge; van den Boogaard, Marie-Jose H.; Bharucha-Goebel, Diana; Donkervoort, Sandra; Winchester, Sara; Zori, Roberto; Bonnemann, Carsten G.; Maroofian, Reza; O'Connor, Emer; Houlden, Henry; Zhao, Fang; Carpen, Olli; White, Matthew; Sreedharan, Jemeen; Stewart, Murray; Ylikallio, Emil; Tyynismaa, Henna
Contributor: University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, HUS Children and Adolescents
University of Helsinki, Department of Pathology
University of Helsinki, HUSLAB
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
Date: 2020-05-01
Language: eng
Number of pages: 14
Belongs to series: Human Molecular Genetics
ISSN: 0964-6906
URI: http://hdl.handle.net/10138/318305
Abstract: Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.
Subject: TREX-2 COMPLEX
SAGA
TRANSCRIPTION
MCM3AP
REGION
SAC3
REPLICATION
INITIATION
PATHWAYS
PROMOTES
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
3111 Biomedicine
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